Blockade of NF-κB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis
Blockade of NF-κB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis
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DOI：
10.1038/sj.onc.1204535
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发表时间：
2001-07-12
期刊：
影响因子：
8
通讯作者：
Fidler, IJ
中科院分区：
文献类型：
--
作者：
Huang, SY;Pettaway, CA;Fidler, IJ
由于核因子-kappaB/relA转录因子在人前列腺癌细胞中被结构性激活，我们在裸鼠原位模型中确定了阻断人前列腺癌细胞中的核因子-kappaB/relA活性是否影响其血管生成、生长和转移。将突变的I kappaBα(I kappaBαM)基因导入高转移的人前列腺癌PC-3M细胞，阻断了核因子-KB的活性。将亲本细胞(PC3M)、对照载体(PC-3M-Neo)和I kappa-BαM(PC-3M-I kappaBαM)细胞分别注射到裸鼠前列腺内。PC3M和PC-3M-Neo细胞生长迅速，区域淋巴结转移，而PC-3M-I kappaBαM细胞生长缓慢，转移潜能低。阻断核因子-kappaB信号通路可显著抑制体内、外三种主要促血管生成分子VEGF、IL-8和MMP-9的表达，从而减少肿瘤血管生成，抑制核因子-kappaB在PC-3M细胞中的活性，还导致基质金属蛋白酶-9mRNA和胶原酶活性的下调，从而减少通过Matrigel的侵袭。总之，这些数据表明，阻断PC-3M细胞中的核因子kappaB活性可以抑制血管生成、侵袭和转移。
Since the NF-kappaB/relA transcription factor is constitutively activated in human prostate cancer cells, we determined whether blocking NF-kappaB/relA activity in human prostate cancer cells affected their angiogenesis, growth, and metastasis in an orthotopic nude mouse model. Highly metastatic PC-3M human prostate cancer cells were transfected with a mutated I kappa -B alpha (I kappaB alphaM), which blocks NF-KB activity. Parental (PC3M), control vector-transfected (PC-3M-Neo), and I kappa -B alphaM-transfected (PC-3M-I kappaB alphaM) cells were injected into the prostate gland of nude mice. PC3M and PC-3M-Neo cells produced rapidly growing tumors and regional lymph node metastasis, whereas PC-3M-I kappaB alphaM cells produced slow growing tumors with low metastatic potential. NF-kappaB signaling blockade significantly inhibited in vitro and in vivo expression of three major proangiogenic molecules, VEGF, IL-8, and MMP-9, and hence decreased neoplastic angiogenesis, Inhibition of NF-kappaB activity in PC-3M cells also resulted in the downregulation of MMP-9 mRNA and collagenase activity, resulting in decreased invasion through Matrigel. Collectively, these data suggest that blockade of NF kappaB activity in PC-3M cells inhibits angiogenesis, invasion, and metastasis.